Genome-wide association study-identified novel genetic loci for QT interval in Taiwan: implications for...

Prolonged QT interval is a well-established marker for malignant ventricular arrhythmias and sudden cardiac death (SCD). Although previous genome-wide association studies (GWASs) have identified multiple QT-associated loci, most were conducted in European cohorts, limiting generalizability to East Asian populations. This study aimed to identify genetic determinants of QTc interval in a Taiwanese population.

A multi-stage GWAS was performed on 13 020 Taiwan Biobank (TWB) participants genotyped using the Axiom Taiwan-specific TWB array, with ∼4.5 million imputed single nucleotide polymorphisms tested. Genome-wide significant loci (P < 5 × 10-8) were taken forwards for validation in an independent cohort of 2011 individuals from the NTU-AF Registry. Functional annotation included cis-expression quantitative trait locus assessment and Bayesian colocalization analyses in relevant cardiac and vascular tissues. Eleven significant loci were identified, including known QT loci/genes (KCNQ1, KCNH2, KCNE1, NOS1AP). Two novel loci-rs55797717 (CD46/MIR29B2CHG) at 1q32.2 and rs76715387 (GJA1) at 6q22.31-were identified and replicated in an independent population. Colocalization analyses linked these variants to gene expression in cardiac and vascular tissues (rs55797717 with CD46 expression in the atrial appendage and MIR29B2CHG in the left ventricle; rs76715387 with GJA1 expression in the tibial artery).

This is the first GWAS of QT interval in a Taiwanese cohort, revealing novel loci at GJA1 and CD46/MIR29B2CHG. These genes may influence ventricular repolarization and susceptibility to SCD through electrotonic load (GJA1), inflammation (CD46), or microRNA (MIR29B2CH).